Machine learning-driven multiscale modeling reveals lipid-dependent dynamics of RAS signaling proteins.

RAS is a signaling protein associated with the cell membrane that is mutated in up to 30% of human cancers. RAS signaling has been proposed to be regulated by dynamic heterogeneity of the cell membrane. Investigating such a mechanism requires near-atomistic detail at macroscopic temporal and spatial scales, which is not possible with conventional computational or experimental techniques. We demonstrate here a multiscale simulation infrastructure that uses machine learning to create a scale-bridging ensemble of over 100,000 simulations of active wild-type KRAS on a complex, asymmetric membrane. Initialized and validated with experimental data (including a new structure of active wild-type KRAS), these simulations represent a substantial advance in the ability to characterize RAS-membrane biology. We report distinctive patterns of local lipid composition that correlate with interfacially promiscuous RAS multimerization. These lipid fingerprints are coupled to RAS dynamics, predicted to influence effector binding, and therefore may be a mechanism for regulating cell signaling cascades.

Exploring CRD mobility during RAS/RAF engagement at the membrane.

During the activation of mitogen-activated protein kinase (MAPK) signaling, the RAS-binding domain (RBD) and cysteine-rich domain (CRD) of RAF bind to active RAS at the plasma membrane. The orientation of RAS at the membrane may be critical for formation of the RAS-RBDCRD complex and subsequent signaling. To explore how RAS membrane orientation relates to the protein dynamics within the RAS-RBDCRD complex, we perform multiscale coarse-grained and all-atom molecular dynamics (MD) simulations of KRAS4b bound to the RBD and CRD domains of RAF-1, both in solution and anchored to a model plasma membrane. Solution MD simulations describe dynamic KRAS4b-CRD conformations, suggesting that the CRD has sufficient flexibility in this environment to substantially change its binding interface with KRAS4b. In contrast, when the ternary complex is anchored to the membrane, the mobility of the CRD relative to KRAS4b is restricted, resulting in fewer distinct KRAS4b-CRD conformations. These simulations implicate membrane orientations of the ternary complex that are consistent with NMR measurements. While a crystal structure-like conformation is observed in both solution and membrane simulations, a particular intermolecular rearrangement of the ternary complex is observed only when it is anchored to the membrane. This configuration emerges when the CRD hydrophobic loops are inserted into the membrane and helices α3-5 of KRAS4b are solvent exposed. This membrane-specific configuration is stabilized by KRAS4b-CRD contacts that are not observed in the crystal structure. These results suggest modulatory interplay between the CRD and plasma membrane that correlate with RAS/RAF complex structure and dynamics, and potentially influence subsequent steps in the activation of MAPK signaling.

ddcMD: A fully GPU-accelerated molecular dynamics program for the Martini force field.

We have implemented the Martini force field within Lawrence Livermore National Laboratory's molecular dynamics program, ddcMD. The program is extended to a heterogeneous programming model so that it can exploit graphics processing unit (GPU) accelerators. In addition to the Martini force field being ported to the GPU, the entire integration step, including thermostat, barostat, and constraint solver, is ported as well, which speeds up the simulations to 278-fold using one GPU vs one central processing unit (CPU) core. A benchmark study is performed with several test cases, comparing ddcMD and GROMACS Martini simulations. The average performance of ddcMD for a protein-lipid simulation system of 136k particles achieves 1.04 µs/day on one NVIDIA V100 GPU and aggregates 6.19 µs/day on one Summit node with six GPUs. The GPU implementation in ddcMD offloads all computations to the GPU and only requires one CPU core per simulation to manage the inputs and outputs, freeing up remaining CPU resources on the compute node for alternative tasks often required in complex simulation campaigns. The ddcMD code has been made open source and is available on GitHub at https://github.com/LLNL/ddcMD.

A generalized Ewald decomposition for screened Coulomb interactions.

Medium-range interactions occur in a wide range of systems, including charged-particle systems with varying screening lengths. We generalize the Ewald method to charged systems described by interactions involving an arbitrary dielectric response function ϵ(𝐤). We provide an error estimate and optimize the generalization to find the break-even parameters that separate a neighbor list-only algorithm from the particle-particle particle-mesh algorithm. We examine the implications of different choices of the screening length for the computational cost of computing the dynamic structure factor. We then use our new method in molecular dynamics simulations to compute the dynamic structure factor for a model plasma system and examine the wave-dispersion properties of this system.

Membrane lipids drive formation of KRAS4b-RAF1 RBDCRD nanoclusters on the membrane.

The oncogene RAS, extensively studied for decades, presents persistent gaps in understanding, hindering the development of effective therapeutic strategies due to a lack of precise details on how RAS initiates MAPK signaling with RAF effector proteins at the plasma membrane. Recent advances in X-ray crystallography, cryo-EM, and super-resolution fluorescence microscopy offer structural and spatial insights, yet the molecular mechanisms involving protein-protein and protein-lipid interactions in RAS-mediated signaling require further characterization. This study utilizes single-molecule experimental techniques, nuclear magnetic resonance spectroscopy, and the computational Machine-Learned Modeling Infrastructure (MuMMI) to examine KRAS4b and RAF1 on a biologically relevant lipid bilayer. MuMMI captures long-timescale events while preserving detailed atomic descriptions, providing testable models for experimental validation. Both in vitro and computational studies reveal that RBDCRD binding alters KRAS lateral diffusion on the lipid bilayer, increasing cluster size and decreasing diffusion. RAS and membrane binding cause hydrophobic residues in the CRD region to penetrate the bilayer, stabilizing complexes through ß-strand elongation. These cooperative interactions among lipids, KRAS4b, and RAF1 are proposed as essential for forming nanoclusters, potentially a critical step in MAP kinase signal activation.

Machine Learning-Driven Multiscale Modeling: Bridging the Scales with a Next-Generation Simulation Infrastructure.

Interdependence across time and length scales is common in biology, where atomic interactions can impact larger-scale phenomenon. Such dependence is especially true for a well-known cancer signaling pathway, where the membrane-bound RAS protein binds an effector protein called RAF. To capture the driving forces that bring RAS and RAF (represented as two domains, RBD and CRD) together on the plasma membrane, simulations with the ability to calculate atomic detail while having long time and large length- scales are needed. The Multiscale Machine-Learned Modeling Infrastructure (MuMMI) is able to resolve RAS/RAF protein-membrane interactions that identify specific lipid-protein fingerprints that enhance protein orientations viable for effector binding. MuMMI is a fully automated, ensemble-based multiscale approach connecting three resolution scales: (1) the coarsest scale is a continuum model able to simulate milliseconds of time for a 1 µm2 membrane, (2) the middle scale is a coarse-grained (CG) Martini bead model to explore protein-lipid interactions, and (3) the finest scale is an all-atom (AA) model capturing specific interactions between lipids and proteins. MuMMI dynamically couples adjacent scales in a pairwise manner using machine learning (ML). The dynamic coupling allows for better sampling of the refined scale from the adjacent coarse scale (forward) and on-the-fly feedback to improve the fidelity of the coarser scale from the adjacent refined scale (backward). MuMMI operates efficiently at any scale, from a few compute nodes to the largest supercomputers in the world, and is generalizable to simulate different systems. As computing resources continue to increase and multiscale methods continue to advance, fully automated multiscale simulations (like MuMMI) will be commonly used to address complex science questions.

Shear-induced anisotropic plastic flow from body-centred-cubic tantalum before melting.

There are many structural and optical similarities between a liquid and a plastic flow. Thus, it is non-trivial to distinguish between them at high pressures and temperatures, and a detailed description of the transformation between these phenomena is crucial to our understanding of the melting of metals at high pressures. Here we report a shear-induced, partially disordered viscous plastic flow from body-centred-cubic tantalum under heating before it melts into a liquid. This thermally activated structural transformation produces a unique, one-dimensional structure analogous to a liquid crystal with the rheological characteristics of Bingham plastics. This mechanism is not specific to Ta and is expected to hold more generally for other metals. Remarkably, this transition is fully consistent with the previously reported anomalously low-temperature melting curve and thus offers a plausible resolution to a long-standing controversy about melting of metals under high pressures.

Efficient Computational Modeling of Human Ventricular Activation and Its Electrocardiographic Representation: A Sensitivity Study.

Patient-specific models of the ventricular myocardium, combined with the computational power to run rapid simulations, are approaching the level where they could be used for personalized cardiovascular medicine. A major remaining challenge is determining model parameters from available patient data, especially for models of the Purkinje-myocardial junctions (PMJs): the sites of initial ventricular electrical activation. There are no non-invasive methods for localizing PMJs in patients, and the relationship between the standard clinical ECG and PMJ model parameters is underexplored. Thus, this study aimed to determine the sensitivity of the QRS complex of the ECG to the anatomical location and regional number of PMJs. The QRS complex was simulated using an image-based human torso and biventricular model, and cardiac electrophysiology was simulated using Cardioid. The PMJs were modeled as discrete current injection stimuli, and the location and number of stimuli were varied within initial activation regions based on published experiments. Results indicate that the QRS complex features were most sensitive to the presence or absence of four "seed" stimuli, and adjusting locations of nearby "regional" stimuli provided finer tuning. Decreasing number of regional stimuli by an order of magnitude resulted in virtually no change in the QRS complex. Thus, a minimal 12-stimuli configuration was identified that resulted in physiological excitation, defined by QRS complex feature metrics and ventricular excitation pattern. Overall, the sensitivity results suggest that parameterizing PMJ location, rather than number, be given significantly higher priority in future studies creating personalized ventricular models from patient-derived ECGs.

Towards real-time simulation of cardiac electrophysiology in a human heart at high resolution.

We have developed the capability to rapidly simulate cardiac electrophysiological phenomena in a human heart discretised at a resolution comparable with the length of a cardiac myocyte. Previous scientific investigation has generally invoked simplified geometries or coarse-resolution hearts, with simulation duration limited to 10s of heartbeats. Using state-of-the-art high-performance computing techniques coupled with one of the most powerful computers available (the 20 PFlop/s IBM BlueGene/Q at Lawrence Livermore National Laboratory), high-resolution simulation of the human heart can now be carried out over 1200 times faster compared with published results in the field. We demonstrate the utility of this capability by simulating, for the first time, the formation of transmural re-entrant waves in a 3D human heart. Such wave patterns are thought to underlie Torsades de Pointes, an arrhythmia that indicates a high risk of sudden cardiac death. Our new simulation capability has the potential to impact a multitude of applications in medicine, pharmaceuticals and implantable devices.

Molecular dynamics simulations and generalized Lenard-Balescu calculations of electron-ion temperature equilibration in plasmas.

We study the problem of electron-ion temperature equilibration in plasmas. We consider pure H at various densities and temperatures and Ar-doped H at temperatures high enough so that the Ar is fully ionized. Two theoretical approaches are used: classical molecular dynamics (MD) with statistical two-body potentials and a generalized Lenard-Balescu (GLB) theory capable of treating multicomponent weakly coupled plasmas. The GLB is used in two modes: (1) with the quantum dielectric response in the random-phase approximation (RPA) together with the pure Coulomb interaction and (2) with the classical (ℏ→0) dielectric response (both with and without local-field corrections) together with the statistical potentials. We find that the MD results are described very well by classical GLB including the statistical potentials and without local-field corrections (RPA only); worse agreement is found when static local-field effects are included, in contradiction to the classical pure-Coulomb case with like charges. The results of the various approaches are all in excellent agreement with pure-Coulomb quantum GLB when the temperature is high enough. In addition, we show that classical calculations with statistical potentials derived from the exact quantum two-body density matrix produce results in far better agreement with pure-Coulomb quantum GLB than classical calculations performed with older existing statistical potentials.

Molecular dynamics simulations of electron-ion temperature equilibration in an SF6 plasma.

We use classical molecular dynamics to investigate electron-ion temperature equilibration in a two-temperature SF6 plasma. We choose a density of 1.0 x 10;{19}SF_{6} molecules per cm;{3} and initial temperatures of T_{e} = 100 eV and T_{S} = T_{F} = 15 eV, in accordance with experiments currently underway at Los Alamos National Laboratory. Our computed relaxation time lies between two oft-used variants of the Landau-Spitzer relaxation formula which invoke static screening. Discrepancies are also found when comparing to the predictions made by more recent theoretical approaches. These differences should be large enough to be measured in the upcoming experiments.

Beyond finite-size scaling in solidification simulations.

Although computer simulation has played a central role in the study of nucleation and growth since the earliest molecular dynamics simulations almost 50 years ago, confusion surrounding the effect of finite size on such simulations has limited their applicability. Modeling solidification in molten tantalum on the Blue Gene/L computer, we report here on the first atomistic simulation of solidification that verifies independence from finite-size effects during the entire nucleation and growth process, up to the onset of coarsening. We show that finite-size scaling theory explains the observed maximal grain sizes for systems up to about 8 000 000 atoms. For larger simulations, a crossover from finite-size scaling to more physical size-independent behavior is observed.

Liquid-liquid phase transition in elemental carbon: a first-principles investigation.

It has been recently suggested that elemental carbon may be a promising candidate to exhibit a liquid-liquid phase transition (LLPT). We report the results of first-principles molecular dynamics simulations showing no evidence of LLPT in carbon, in the same temperature and pressure range where such a transition was found using empirical calculations. Our simulations indicate a continuous evolution from a primarily sp-bonded liquid to an sp(2)-like and an sp(3)-like fluid, as a function of pressure, above the graphite melting line. The discrepancy between quantum and classical simulations is attributed to the inability of empirical potentials to describe complex electronic effects in condensed carbon phases.